Restoration of hepatic glucokinase expression corrects hepatic glucose flux and normalizes plasma glucose in zucker diabetic fatty rats.
OBJECTIVE
We examined in 20-week-old Zucker diabetic fatty (ZDF) rats whether restoration of hepatic glucokinase (GK) expression would alter hepatic glucose flux and improve hyperglycemia.


METHODS
ZDF rats were treated at various doses with an adenovirus that directs the expression of rat liver GK (AdvCMV-GKL) dose dependently, and various metabolic parameters were compared with those of nondiabetic lean littermates (ZCL rats) before and during a hyperglycemic clamp. Viral infection per se did not affect hepatic GK activity, since expression of a catalytically inactive form of GK did not alter endogenous hepatic GK activity.


RESULTS
ZDF rats compared with ZCL rats have lower hepatic GK activity (11.6 +/- 1.9 vs. 32.5 +/- 3.2 mU/mg protein), marked hyperglycemia (23.9 +/- 1.2 vs. 7.4 +/- 0.3 mmol/l), higher endogenous glucose production (80 +/- 3 vs. 38 +/- 3 micromol x kg(-1) x min(-1)), increased glucose-6-phosphatase flux (150 +/- 11 vs. 58 +/- 8 micromol x kg(-1) x min(-1)), and during a hyperglycemic clamp, a failure to suppress endogenous glucose production (80 +/- 7 vs. -7 +/- 4 micromol x kg(-1) x min(-1)) and promote glucose incorporation into glycogen (15 +/- 5 vs. 43 +/- 3 micromol/g liver). Treatment of ZDF rats with different doses of AdvCMV-GKL, which restored hepatic GK activity to one to two times that of ZCL rats, normalized plasma glucose levels and endogenous glucose production. During a hyperglycemic clamp, glucose production was suppressed and glucose incorporation into glycogen was normal.


CONCLUSIONS
Alteration of hepatic GK activity in ZDF rats has profound effects on plasma glucose and hepatic glucose flux.
Torres
Tracy P
TP
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Catlin
Reetta L
RL
Chan
Robert
R
Fujimoto
Yuka
Y
Sasaki
Noriyasu
N
Printz
Richard L
RL
Newgard
Christopher B
CB
Shiota
Masakazu
M
D000256:Adenoviridae / Q000235:genetics; D000375:Aging; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D015153:Blotting, Western; D001835:Body Weight; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D005934:Glucagon / Q000097:blood; D005941:Glucokinase / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006943:Hyperglycemia / Q000097:blood / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000097:blood; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D051381:Rats; D011924:Rats, Zucker
D001786:Blood Glucose; D002352:Carrier Proteins; D007328:Insulin; C080906:glucokinase regulatory protein; D005934:Glucagon; D005941:Glucokinase; D005947:Glucose